Nilotinib

Base Information

• Chemical Name: Nilotinib
• CAS No.: 641571-10-0
• Molecular Formula: C28H22F3N7O
• Molecular Weight: 529.524
• Hs Code.: 29335990
• European Community (EC) Number: 700-544-5,692-062-6
• NSC Number: 747599
• UNII: F41401512X
• DSSTox Substance ID: DTXSID5042663
• Nikkaji Number: J2.203.300J
• Wikipedia: Nilotinib
• Wikidata: Q412327
• NCI Thesaurus Code: C48375
• RXCUI: 662281
• Pharos Ligand ID: HBA97ATR7TC8
• Metabolomics Workbench ID: 43635
• ChEMBL ID: CHEMBL255863
• Mol file: 641571-10-0.mol

Synonyms:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide;AMN 107;AMN-107;AMN107;benzamide, 4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-(3-pyridinyl)-2-pyrimidinyl)amino)-, hydrochloride (1:1);benzamide, 4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-(3-pyridinyl)-2-pyrimidinyl)amino)-, hydrochloride, hydrate;benzamide, 4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-(3-pyridinyl)-2-pyrimidinyl)amino)-, hydrochloride, hydrate (1:1:2);benzamide, 4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-(3-pyridinyl)-2-pyrimidinyl)amino)-, hydrochloride, hydrate (1:2:2);benzamide, 4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-(3-pyridinyl)-2-pyrimidinyl)amino)-, hydrochloride, hydrate (2:2:3);nilotinib;nilotinib dihydrochloride dihydrate;nilotinib hydrochloride;nilotinib hydrochloride anhydrous;nilotinib hydrochloride dihydrate;nilotinib hydrochloride hydrate;nilotinib hydrochloride monohydrate;nilotinib hydrochloride sesquihydrate;Tasigna

Chemical Property of Nilotinib

Chemical Property:

• Appearance/Colour: off-white solid
• Melting Point: 231-233 °C
• Refractive Index: 1.65
• PSA: 97.62000
• Density: 1.362 g/cm³
• LogP: 6.50180
• Storage Temp.: -20°C Freezer
• Solubility.: Soluble in DMSO (up to 50 mg/ml)
• XLogP3: 4.9
• Hydrogen Bond Donor Count: 2
• Hydrogen Bond Acceptor Count: 9
• Rotatable Bond Count: 6
• Exact Mass: 529.18379284
• Heavy Atom Count: 39
• Complexity: 817

Purity/Quality:

99.9% ^*data from raw suppliers

Nilotinib-d6 ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Antineoplastic Agents
• Canonical SMILES: CC1=C(C=C(C=C1)C(=O)NC2=CC(=CC(=C2)C(F)(F)F)N3C=C(N=C3)C)NC4=NC=CC(=N4)C5=CN=CC=C5
• Recent ClinicalTrials: Study of Efficacy and Safety of Asciminib in Combination With Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP)
• Recent EU Clinical Trials: A phase IIIb, multi-center, open-label, randomized study of tolerability and efficacy of oral asciminib versus nilotinib in patients with newly diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase
• Recent NIPH Clinical Trials: A clinical trial of dasatinib vs. nilotinib in children with CP- and AP-CML
• Drug Interactions: Nilotinib is a competitive inhibitor of cytochrome P-450 (CYP) isoenzymes 3A4, 2C8, 2C9, and 2D6 and has the potential to increase concentrations of drugs metabolized by these enzymes. Nilotinib plasma concentration is increased during concomitant use with potent CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Decreased nilotinib plasma concentration occurs during concomitant use with potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort). Drugs that increase the pH of the upper gastrointestinal tract may decrease the solubility of nilotinib and reduce its bioavailability. The oral administration of esomeprazole resulted in a 34% reduction in the AUC of nilotinib.
• Description: Chronic myeloid leukemia (CML), a hematological stem-cell disorder, is definitively diagnosed by the detection of the Philadelphia chromosome, a truncated version of chromosome 22 resulting from the reciprocal translocation of chromosomes 9 and 22 induced by a single mutagenic event. The consequence is the juxtaposition of two genes creating a fusion gene BCR-ABL. This gene leads to the translation of a fusion protein with increased tyrosine kinase activity that contributes to the pathogenesis of CML. Targeting the BCR-ABL protein has led to the successful intervention of the disease. Now established as first-line therapy for CML, imatinib was the first selective tyrosine kinase inhibitor of BCR-ABL. Since imatinib only binds to an inactive conformation of the ABL kinase portion, the conformational restrictions contribute to its selectivity.
• Uses: Nilotinib, an orally active signal transduction inhibitor that selectively inhibits the tyrosine kinase Bcr-Abl, was discovered and developed by Norvartis and was launched for the treatment of chronic myeloid leukemia (CML) in patients with Philadelphia chromosome-positive (Ph+) disease who are resistant or intolerant to imatinib mesilate. Additional clinical trials are currently underway for the treatment of acute lymphoblastic leukemia (ALL) and gastrointestinal stromal tumors (GISTs). Nilotinib (AMN-107) is a Bcr-Abl inhibitor with IC50 less than 30 nM. Nilotinib-d6, is the labeled analogue of Nilotinib, which might be useful in treatment of chronic myelogenous leukemia.
• Clinical Use: Tyrosine kinase inhibitor: Treatment of chronic myelogenous leukaemia (CML)
• Drug interactions: Potentially hazardous interactions with other drugs Antibacterials: avoid with clarithromycin, rifampicin (concentration reduced) and telithromycin. Antifungals: avoid with itraconazole, ketoconazole (concentration increased) and voriconazole. Antipsychotics: avoid with clozapine (increased risk of agranulocytosis). Antivirals: avoid with boceprevir and ritonavir (concentration possibly increased). Grapefruit juice: avoid concomitant administration. Avoid concomitant use with other inhibitors or inducers of CYP3A4. Dose alterations may be required.

Technology Process of Nilotinib

There total 52 articles about Nilotinib which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 100.0%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + carbon monoxide (201230-82-2) + 5-bromo-2-methylphenyl(4-(pyridin-3-yl)pyrimidin-2-yl)-carbamic acid tert-butyl ester → nilotinib (641571-10-0)

Guidance literature:

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline; carbon monoxide; 5-bromo-2-methylphenyl(4-(pyridin-3-yl)pyrimidin-2-yl)-carbamic acid tert-butyl ester; With bis(benzonitrile)palladium(II) dichloride; triethylamine; 1,2-bis-(diphenylphosphino)ethane; phenol; In N,N-dimethyl-formamide; at 90 - 105 ℃; for 48h; under 6000.6 Torr; Molecular sieve; Inert atmosphere; Autoclave;

With trifluoroacetic acid; In ethanol; Inert atmosphere;

With potassium hydroxide; In ethanol; water; pH=6 - 9; Reagent/catalyst; Solvent; Pressure; Inert atmosphere;

Reference yield: 95.2%

4-methyl-N-[3-(4-methyl-1H-imidazolyl)-5-trifluoromethylphenyl]-3-guanidinobenzamide nitrate + 3-(N,N-dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one (55314-16-4,75415-01-9,123367-26-0) → nilotinib (641571-10-0)

Guidance literature:

With sodium hydroxide; In ethanol; for 40h; Reagent/catalyst; Reflux;

Reference yield: 94.0%

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (641571-11-1) + 4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzoic acid (641569-94-0) → nilotinib (641571-10-0)

Guidance literature:

4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzoic acid; With thionyl chloride; In 1-methyl-pyrrolidin-2-one; at 60 ℃; for 1.25h;

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline; In 1-methyl-pyrrolidin-2-one; at 90 ℃; for 3h; Product distribution / selectivity;

upstream raw materials:

3-iodo-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]benzamide

4-pyridin-3-ylpyrimidin-2-ylamine

3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline

methyl 4-methyl-3 -[[4-(pyridin-3-yl)pyrimidin-2-yl]amino]benzoate

Downstream raw materials:

nilotinib trihydrochloride

Refernces

• 1、 -. "High-yield synthesis method of nilotinib". Paragraph 0008; 0023; 0028-0031; 0036-0040; 0045-0048. . Retrieved 2020/03/17.
• 2、 -. "AN IMPROVED PROCESS FOR 3-(4-METHYL-1H-IMIDAZOL-1-YL)-5-(TRIFLUOROMETHYL) ANILINE". Page/Page column 24-25. . Retrieved 2019/07/17.